Compounds having antihypertensive and anti-ischemic properties

ABSTRACT

This invention relates to adenosine derivatives and analogs which possess adenosine agonist activity and are useful as anti-hypertensive and anti-ischemic agents, to pharmaceutical compositions including such compounds, and to their use in treating hypertension and myocardial ischemia, and to methods and intermediates used in the preparation of such compounds.

This application is a continuation-in-part application of co-pendingU.S. application Ser. No. 07/587,884, filed Sep. 25, 1990 now abandoned,and priority benefit is also claimed, pursuant to 37 U.S.C. §§ 120 and363, to co-pending PCT Application PCT/US91/06990, filed Sep. 25, 1991.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds derived from adenosine and analogsthereof, to pharmaceutical compositions containing such compounds, totheir use in treating hypertension and myocardial ischemia, and tomethods and intermediates used in the preparation of such compounds.

Hypertension

Hypertension, a condition of elevated blood pressure, affects asubstantial number of the human population. Consequences of persistenthypertension include vascular damage to the ocular, renal, cardiac andcerebral systems, and the risk of these complications increases as bloodpressure increases. Basic factors controlling blood pressure are cardiacoutput and peripheral vascular resistance, with the latter being thepredominant common mechanism which is controlled by various influences.The sympathetic nervous system regulates peripheral vascular resistancethrough direct effects on alpha- and beta-adrenergic receptors as wellas through indirect effects on renin release. Drug therapy is aimed atspecific components of these blood pressure regulatory systems, withdifferent mechanisms of action defining the several drug classesincluding diuretics, beta-adrenergic receptor antagonists(beta-blockers), angiotensin-converting enzyme (ACE) inhibitors, andcalcium channel antagonists.

Thiazide-type diuretics are used in hypertension to reduce peripheralvascular resistance through their effects on sodium and water excretion.This class of drugs includes hydrochlorothiazide, chlorothiazide,methyclothiazide, and cyclothiazide, as well as related agentsindapamide, metolazone, and chlorthalidone. Although the beta-blockermechanism of action was once believed to be blockade of the beta₁-adrenergic receptor subtype in the heart to reduce heart rate andcardiac output, more recent beta-blockers with intrinsic sympathomimeticactivity (ISA), including pindolol, acebutolol, penbutolol, andcarteolol, are as effective as non-ISA beta-blockers, causing lessreduction in heart rate and cardiac output. Other postulated mechanismsfor these drugs include inhibition of renin release, a central effect,and an effect at pre-synaptic beta-adrenergic receptors resulting ininhibition of norepinephrine release. Cardioselective beta-blockersmetoprolol (Lopressor-Geigy), acebutolol (Sectral-Wyeth), and atenolol(Tenormin-ICI), at low doses, have a greater effect on beta₁ -adrenergicreceptors than on beta₂ -adrenergic receptor subtypes located in thebronchi and blood vessels. Nonselective beta-blockers act on bothbeta-adrenergic receptor subtypes and include propranolol(Inderal-Ayerst), timolol (Blocadren-Merck), nadolol (Corgard-Squibb),pindolol (Visken-Sandoz), penbutolol (Levatol-Hoechst-Roussel), andcarteolol (Cartrol-Abbott). Adverse effects of beta-blockers includeasymptomatic bradycardia, exacerbation of congestive heart failure,gastrointestinal disturbances, increased airway resistance, maskedsymptoms of hypoglycemia, and depression. They may cause elevation ofserum triglycerides and may lower high-density lipoprotein cholesterol.

ACE inhibitors prevent the formation of angiotensin II and inhibitbreakdown of bradykinin. Angiotensin II is a potent vasoconstrictor andalso stimulates the secretion of aldosterone. By producing blockade ofthe renin-angiotensin-aldosterone system, these agents decreaseperipheral vascular resistance, as well as sodium and water retention.In addition, ACE inhibitors increase levels of bradykinin andprostaglandins, endogenous vasodilators. Captopril (Capoten-Squibb) andEnalapril (Vasotec-Merck) are the leading ACE inhibitors. Adverseeffects of the ACE inhibitors include rash, taste disturbance,proteinuria, and neutropenia.

The calcium channel antagonists reduce the influx of calcium intovascular smooth muscle cells and produce systemic vasodilation,resulting in their antihypertensive effect. Other effects of calciumchannel antagonists include interference with action of angiotensin IIand alpha₂ -adrenergic receptor blockade, which may add to theirantihypertensive effects. Calcium channel antagonists do not have theadverse metabolic and pharmacologic effects of thiazides orbeta-blockers and may therefore be useful in patients with diabetes,peripheral vascular disease, or chronic obstructive pulmonary disease.Two calcium channel antagonists, Verapamil and diltiazem, have seriousadverse cardiovascular effects on atrioventricular cardiac conduction inpatients with preexisting conduction abnormalities, and they may worsenbradycardia, heart block, and congestive heart failure. Other minoradverse effects of calcium channel antagonists include peripheral edema,dizziness, light-headedness, headache, nausea, and flushing, especiallywith nifedipine and nicardipine.

Many other agents are available to treat essential hypertension. Theseagents include prazosin and terazocin, alpha₁ -adrenergic receptorantagonists whose antihypertensive effects are due to resultant arterialvasodilation; clonidine, an alpha₂ -adrenergic agonist which actscentrally as well as peripherally at inhibitory alpha₂ -adrenergicreceptors, decreasing sympathetic response. Other centrally actingagents include methyldopa, guanabenz, and guanfacine; reserpine, whichacts by depleting stores of catecholamines; guanadrel, a peripheraladrenergic antagonist similar to guanethidine with a shorter duration ofaction; and direct-acting vasodilators such as hydralazine andminoxidil. These agents, although effective, produce noticeablesymptomatic side effects, including reflex sympathetic stimulation andfluid retention, orthostatic hypotension, and impotence.

Many antihypertensive agents activate compensatory pressor mechanisms,such as increased renin release, elevated aldosterone secretion andincreased sympathetic vasoconstrictor tone, which are designed to returnarterial pressure to pretreatment levels, and which can lead to salt andwater retention, edema and ultimately to tolerance to theantihypertensive actions of the agent. Furthermore, due to the widevariety of side effects experienced with the present complement ofantihypertensive drugs and the problems experienced therewith by specialpopulations of hypertensive patients, including the elderly, blacks, andpatients with chronic obstructive pulmonary disease, diabetes, orperipheral vascular diseases, there is a need for additional classes ofdrugs to treat hypertension.

Ischemia

Myocardial ischemia is the result of an imbalance of myocardial oxygensupply and demand and includes exertional and vasospastic myocardialdysfunction. Exertional ischemia is generally ascribed to the presenceof critical atherosclerotic stenosis involving large coronary arteriesresulting in a reduction in subendocardial flow. Vasospastic ischemia isassociated with a spasm of focal variety, whose onset is not associatedwith exertion or stress. The spasm is better defined as an abruptincrease in vascular tone. Mechanisms for vasospastic ischemia include:(i) Increased vascular tone at the site of stenosis due to increasedcatecholamine release: (ii) Transient intraluminal plugging and (iii)Release of vasoactive substances formed by platelets at the site ofendothelial lesions.

The coronary circulation is unique since it perfuses the organ whichgenerates the perfusion pressure for the entire circulation. Thus,interventions which alter the state of the peripheral circulation andcontractility will have a profound effect on coronary circulation. Theregulatory component of the coronary vasculature is the small coronaryarterioles which can greatly alter their internal diameter. Thealteration of the internal radius is the result of either intrinsiccontraction of vascular smooth muscle (autoregulation) or extravascularcompression due to ventricular contraction. The net effect of therapieson the ischemic problem involves a complex interaction of opposingfactors which determine the oxygen supply and demand.

The present invention relates to the class of adenosine agonists andtheir utility in the treatment of hypertension and myocardial ischemia.

2. Reported Developments

Adenosine has a wide variety of physiological and pharmacological actionincluding a marked alteration of cardiovascular and renal function. Inanimals and man, intravenous injection of the adenosine nucleotidecauses hypotension.

The physiological and pharmacological actions of adenosine are mediatedthrough specific receptors located on cell surfaces. Two adenosinereceptor subtypes, designated as A₁ and A₂ receptors, have beenidentified. The A₁ receptor inhibits the formation of cAMP bysuppressing the activity of adenylate cyclase, while stimulation of A₂receptors increases adenylate cyclase activity and intracellular cAMP.Each receptor appears to mediate specific actions of adenosine indifferent tissues: for example, the vascular actions of adenosineappears to be mediated through stimulation of A₂ receptors, which issupported by the positive correlation between cAMP generation andvasorelaxation in adenosine-treated isolated vascular smooth muscle;while stimulation of the cardiac A₁ receptors reduces cAMP generation inthe heart which contributes to negative dromotropic, inotropic andchronotropic cardiac effects. Consequently, unlike most vasodilators,adenosine administration does not produce a reflex tachycardia.

Adenosine also exerts a marked influence on renal function. Intrarenalinfusion of adenosine causes a transient fall in renal blood flow and anincrease in renal vascular resistance. With continued infusion ofadenosine, renal blood flow returns to control levels and renal vascularresistance is reduced. The initial renal vasoconstrictor responses toadenosine are not due to direct vasoconstrictor actions of thenucleotide, but involve an interaction between adenosine and therenin-angiotensin system.

Adenosine is widely regarded as the primary physiological mediator ofreactive hyperemia and autoregulation of the coronary bed in response tomyocardial ischemia. It has been reported that the coronary endotheliumpossesses adenosine A₂ receptors linked to adenylate cyclase, which areactivated in parallel with increases in coronary flow and thatcardiomyocyte receptors are predominantly of the adenosine A₁ subtypeand associated with bradycardia. Accordingly, adenosine offers a uniquemechanism of ischemic therapy.

Cardiovascular responses to adenosine are short-lived due to the rapiduptake and metabolism of the endogenous nucleotide. In contrast, theadenosine analogs are more resistant to metabolic degradation and arereported to elicit sustained alterations in arterial pressure and heartrate.

Several potent metabolically-stable analogs of adenosine have beensynthesized which demonstrate varying degrees of selectivity for the tworeceptor subtypes. Adenosine agonists have generally shown greaterselectivity for A₁ receptors as compared to A₂ receptors.Cyclopentyladenosine (CPA) and R-phenylisopropyl-adenosine (R-PIA) arestandard adenosine agonists which show marked selectivity for the A₁receptor (A₂ /A₁ ratio=780 and 106, respectively). In contrast,N-5'-ethyl-carboxamido adenosine (NECA) is a potent A₂ receptor agonist(Ki-12 nM) but has equal affinity for the A₁ receptor (Ki-6.3 nM; A₂ /A₁ration=1.87). Until recently, CV-1808 was the most selective A₂ agonistavailable (A₂ /A₁ =0.19), even though the compound was 10-fold lesspotent than NECA in its affinity for the A₂ receptor. In recentdevelopments, newer compounds have been disclosed which are very potentand selective A₂ agonists (Ki=3-8 nM for A₂ /A₁ ratio=0.027-0.042).

Various N6-aryl and N6-heteroarylalkyl substituted adenosines, andsubstituted-(2-amino and 2-hydroxy)adenosines, have been reported in theliterature as possessing varied pharmacological activity, includingcardiac and circulatory activity. See, for example, British PatentSpecification 1,123,245, German Offen. 2,136,624, German Off 2,059,922,German Offen. 2,514,284, South African Patent No. 67/7630, U.S. Pat. No.4,501,735, EP Publication No. 0139358 (disclosing N6-[geminal diarylsubstituted alkyl]adenosines), EP Patent Application Ser. No. 88106818.3(disclosing that N6-heterocyclic-substituted adenosine derivativesexhibit cardiac vasodilatory activity), German Often. 2,131,938(disclosing aryl and heteroaryl alkyl hydrazinyl adenosine derivatives),German Often. 2,151,013 (disclosing N6-aryl and heteroaryl substitutedadenosines), German Often. 2,205,002 (disclosing adenosines withN6-substituents comprising bridged ring structures linking theN6-nitrogen to substituents including thienyl) and South African PatentNo. 68/5477 (disclosing N6-indolyl substituted-2-hydroxy adenosines).

U.S. Pat. No. 4,954,504 and EP Publication No. 0267878 disclosegenerically that carbocyclic ribose analogues of adenosine, andpharmaceutically acceptable esters thereof, substituted in the 2- and/orN6-positions by aryl lower alkyl groups including thienyl,tetrahydropyranyl, tetrahydrothiopyranyl, and bicyclic benzo fused 5- or6- membered saturated heterocyclic lower alkyl derivatives exhibitadenosine receptor agonist properties. Adenosine analogues havingthienyl-type substituents are described in EP Publication No. 0277917(disclosing N6-substituted-2-heteroarylalkylamino substituted adenosinesincluding 2-[(2-[thien-2-yl]ethyl)amino] substituted adenosine), GermanOften. 2,139,107 (disclosing N6-[benzothienylmethyl]-adenosine), PCT WO85/04882 (disclosing that N6-heterocyclicalkyl-substituted adenosinederivatives, includingN6-[2-(2thienyl)ethyl]amino-9-(D-ribofuranosyl)-9H-purine, exhibitcardiovascular vasodilatory activity and that N6-chiral substituentsexhibit enhanced activity), EP Published Application No. 0232813(disclosing that N6-(1-substituted thienyl)cyclopropylmethyl substitutedadenosines exhibit cardiovascular activity), U.S. Pat. No. 4,683,223(disclosing that N6-benzothiopyranyl substituted adenosines exhibitantihypertensive properties), PCT WO 88/03147 and WO 88/03148(disclosing that N6-[2-aryl-2-(thien-2-yl)]ethyl substituted adensosinesexhibit antihypertensive properties), U.S. Pat. Nos. 4,636,493 and4,600,707 (disclosing that N6-benzothienylethyl substituted adenosinesexhibit antihypertensive properties).

Adenosine-5'-carboxylic acid amides are disclosed as having utility asanti-hypertensive and anti-anginal agents in U.S. Pat. No. 3,914,415,while U.S. Pat. No. 4,738,954 discloses that N6-substituted aryl andarylalkyl-adenosine 5'-ethyl carboxamides exhibit various cardiac andantihypertensive properties.

N⁶ -alkyl-2'-O-alkyl adenosines are disclosed in EP Publication No.0,378,518 and UK Patent Application 2,226,027 as having antihypertensiveactivity. N⁶ -alkyl-2',3'-di-O-alkyl adenosines are also reported tohave utility as antihypertensive agents, U.S. Pat. No. 4,843,066.

Adenosine-5'-(N-substituted)carboxamides and carboxylate esters andN1-oxides thereof are reported to be coronary vasodilators, Stein, etal., J. Med. Chem. 1980, 23, 313-319 and J. Med. Chem. 19 (10), 1180(1976). Adenosine-5'-carboxamides and N1-oxides thereof are alsoreported as small animal poisons in U.S. Pat. No. 4,167,565.

It is believed that the reported toxicity, CNS properties and heart rateelevation associated with adenosine analogues have contributed to thedifficulties preventing the development of a commercial adenosine analogantihypertensive/antiischemic agent. The present invention relates to aclass of metabolically stable adenosine agonists, and derivativesthereof, possessing unexpectedly desireable pharmacological properties,i.e. are anti-hypertensive and anti-ischemic agents having a uniquetherapeutic profile.

Summary of the Invention

The compounds of the present invention are described by Formula I##STR1## wherein K is N, N→O, or CH;

Q is CH₂ or O;

T is R₂ ##STR2## or R₃ O--CH₂ ; X is a straight or branched chainalkylene, cycloalkylene or cycloalkenylene group;

Y is NR₄, O or S;

a=0 or 1;

Z is of the formula ##STR3## Z₁ is N, CR₅, (CH)_(m) --CR₅ or (CH)_(m)--N, m being 1 or 2;

Z₂ is N, NR₆, O or S, n being 0 or 1;

R₁, R₂, R₃, R₄, R₅ and R₆ are independently H, alkyl, aryl orheterocyclyl;

R_(a) and R_(b) are independently H, OH, alkyl, hydroxyalkyl, alkylmercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino,carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl orheterocyclyl; and

R' and R" are independently hydrogen, alkyl, aralkyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,aryloxycarbonyl, or R' and R" together may form ##STR4## where R_(c) ishydrogen or alkyl, ##STR5## where R_(d) and R_(e) are independentlyhydrogen, alkyl, or together with the carbon atom to which they areattached may form a 1,1-cycloalkyl group;

provided that when X is straight chain alkylene and Q is oxygen, then Zrepresents a heterocyclyl including at least two heteroatoms;

or a pharmaceutically acceptable salt thereof.

This invention relates also to methods for treating cardiovasculardisease marked by hypertension or myocardial ischemia usingpharmaceutical compositions including an anti-hypertensive effectiveamount or an anti-ischemic effective amount of a compound of Formula Iabove, and to methods and intermediates used in the preparation of suchcompounds.

DETAILED DESCRIPTION

As used above and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

"Acyl" means a straight or branched alkyl-C=0 group. Preferred acylgroups are lower alkanoyl having from 1 to about 6 carbon atoms in thealkyl group.

"Alkyl" means a saturated aliphatic hydrocarbon group which may bestraight or branched and having about 1 to about 20 carbon atoms in thechain. Branched means that a lower alkyl group such as methyl, ethyl orpropyl is attached to a linear alkyl chain.

"Lower alkyl" means an alkyl group having 1 to about 6 carbons.

"Alkylene" means a straight or branched bivalent hydrocarbon chainhaving from 1 to about 20 carbon atoms. The preferred alkylene groupsare the lower alkylene groups having from 1 to about 6 carbon atoms. Themost preferred alkylene groups are methylene, ethylene, ethylethylene,methylethylene and dimethylethylene.

"Cycloalkylene" means a 1,2- or 1,3-bivalent carbocyclic group havingabout 4 to about 8 carbon atoms. Preferred cycloalkylene groups include4, 5-cis- or trans-cyclohexenylene, 1,2-cyclohexanylene and1,2-cyclopentylene.

"Alkyl amino" means an amino group substituted by one or two alkylgroups. Preferred groups are the lower alkyl amino groups.

"Alkyl carbamoyl" means a carbamoyl group substituted by one or twoalkyl groups. Preferred are the lower alkyl carbamoyl groups.

"Alkyl mercaptyl" means an alkyl group substituted by a mercaptyl group.Mercaptyl lower alkyl groups are preferred.

"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previouslydescribed. Lower alkoxy groups are preferred. Exemplary groups includemethoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Alkoxyalkyl" means an alkyl group, as previously described, substitutedby an alkoxy group, as previously described.

"Aralkyl" means an alkyl group substituted by an aryl radical, wherein"aryl" means a phenyl or phenyl substituted with one or moresubstituents which may be alkyl, alkoxy, amino, nitro, carboxy,carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl,alkylmercaptyl, carbalkyl or carbamoyl.

"Carbalkoxy" means a carboxyl substituent esterified with an alcohol ofthe formula C_(n) H_(2n+1) OH, wherein n is from 1 to about 6.

"Halogen" (or "halo") means chlorine (chloro), fluorine (fluoro),bromine (bromo) or iodine (iodo).

"Heterocyclyl" means about a 4 to about a 10 membered ring structure inwhich one or more of the atoms in the ring is an element other thancarbon, e.g., N, O, or S.

Representative heterocyclic moieties comprising the N6 substituent ofthe compounds of Formula I include the following: ##STR6##

Preferred heterocyclic groups include unsubstituted and substitutedthienyl, thiazolyl and benzothiazolyl groups, wherein the substituentsmay be one or more members of the group of alkoxy, alkylamino, aryl,carbalkoxy, carbamoyl, cyano, halo, hydroxy, mercaptyl, alkylmercaptylor nitro.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.Hydroxy lower alkyl groups are preferred. Exemplary preferred groupsinclude hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and3-hydroxypropyl.

"Pro-drug" means a compound which may or may not itself be biologicallyactive but which may, by metabolic, solvolytic, or other physiologicalmeans be converted to a biologically active chemical entity.

The compounds of Formula I include preferably a chiral (asymmetric)center. For example, preferred compounds having such asymmetric centercomprise compounds e.g., wherein X is isopropylene, and have either an Ror S configuration, the R configuration being most preferred. Theinvention includes the individual stereoisomers and mixtures thereof.The individual isomers are prepared or isolated by methods well known inthe art or by methods described herein.

The compounds of the invention may be used in the form of the free base,in the form of acid addition salts or as hydrates. All such forms arewithin the scope of the invention. Acid addition salts are simply a moreconvenient form for use. In practice, use of the salt form inherentlyamounts to use of the base form. The acids which may be used to preparethe acid addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are non-toxic to the recipient in pharmaceuticaldoses of the salts, so that the beneficial anti-hypertensive andanti-ischemic effects produced by the free base are not vitiated by sideeffects ascribable to the anions. Although pharmaceutically acceptablesalts of the compounds of the invention are preferred, all acid additionsalts are useful as sources of the free base form, even if theparticular salt, per se, is desired only as an intermediate product as,for example, when the salt is formed only for purposes of purificationand identification, or when it is used as an intermediate in preparing apharmaceutically acceptable salt by ion exchange procedures.Pharmaceutically acceptable salts within the scope of the invention arethose derived from the following acids: mineral acids such ashydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid;and organic acids such as acetic acid, citric acid, lactic acid,tartaric acid, malonic acid, methanesulfonic acid, fumaric acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid and the like. The correspondingacid addition salts comprise the following: hydrochloride, sulfate,phosphate, sulfamate, acetate, citrate, lactate, tartarate,methanesulfonate, fumarate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, cyclohexylsulfonate and quinate, respectively.

The acid addition salts of the compounds of the invention areconveniently prepared either by dissolving the free base in aqueous oraqueous-alcohol solution or other suitable solvents containing theappropriate acid and isolating the salt by evaporating the solution, orby reacting the free base and acid in an organic solvent, in which casethe salt separates directly or can be obtained by concentration of thesolution.

Included within the scope of Formula I are classes of compounds whichmay be characterized generally as N6-heterocyclic-substitutedadenosines; N6-heterocyclic-substituted carbocyclic adenosines (or,alternatively, dihydroxy[N6-heterocyclicsubstituted-9-adenyl]cyclopentanes) and N-oxides thereof; andN6-heterocyclic-substituted-N'-1-deazaaristeromycins (or, alternatively,dihydroxy[N7-heterocyclic-substituted[4,5-b]imidazopyridyl]-cyclopentanes).Also within the scope of Formula I are the 5'-alkylcarboxamidederivatives of the adenosines, the carbocyclic adenosines and the1-deazaaristeromycins, the derivatives of compounds of the above classesin which one or both of the 2- or 3- hydroxyl groups of the cyclopentanering or, in the cases of classes of compounds containing the ribosemoiety, the 2'- or 3'-hydroxyl groups of the ribose ring aresubstituted. Such derivatives may themselves comprise the biologicallyactive chemical entity useful in the treatment of hypertension andmyocardial ischemia, or may act as pro-drugs to such biologically activecompounds which are formed therefrom under physiological conditions.

Representative compounds of the invention include:N6-[trans-2-(thiophen-2-yl)cyclohex-4-en-1-yl]adenosine;N6-[trans-2-(thiophen-3-yl)-cyclohex-4-en-1 -yl]adenosine;N6-[trans-2-(thiophen-2-yl)cyclohex-4-en-1 -yl]adenosine-5'-N-ethylcarboxamide; N6-[2-(2'-aminobenzothiazolyl)ethyl]adenosine;N6-[2-(2'-thiobenzothiazolyl)ethyl]adenosine;N6-[2-(6'-ethoxy2'-thiobenzothiazolyl)ethyl]adenosine;N6-[2-(2'-aminobenzothiazolyl)ethyl]adenosine-5'-N-ethyl carboxamide;N6-[2-(2'-aminothiazolyl)ethyl]carbocyclic adenosine-5'-N-ethylcarboxamide; N6-[2-(4'-methylthiazol-5'-yl)ethyl]adenosine;N6-[2-(2'-thiazolyl)ethyl]adenosine;N6-[(R)-1-(5'-chlorothien-2'-yl)2-propyl]adenosine-5'-N-ethylcarboxamide; N6-[2-(2'-methyl-4'-thiazolyl)ethyl]adenosine; N6-[(R)-1-methyl-2-(2'-benzo[b]thiophenyl)ethyl]adenosine;N6-[2-(4"-methyl-5"-thiazolyl)ethyl]carbocyclic adenosine-5' -N-ethylcarboxamide; N6-[2-(2"-thiazolyl)ethyl]carbocyclic adenosine-5'-N-ethylcarboxamide; N6-[2-( 4'-phenyl-2'-thiazolyl)ethyl]adenosine;N6-[(R)-1-(5"-chloro-2"-thienyl)prop-2-yl]carbocyclicadenosine-5'-N-ethyl carboxamide;(-)-N6-[thiophen-2"-yl)ethan-2-yl]carbocyclic adenosine-5'-N-ethylcarboxamide; N6-[1-(thiophen-3-yl)ethan-2-yl]carbocyclicadenosine-5'-N-ethyl carboxamide;N6-[(R)-1-((thiophen-2-yl)prop-2-yl)]carbocyclic adenosine-5'-N-ethylcarboxamide;N6-[1-(thiophen-2-yl)ethan-2-yl]-N'-1-deazaaristeromycin-5'-N-ethylcarboxamide; N6-[(R)-1-((thiazo-2-yl)-prop-2-yl)]adenosine-5'-N-ethylcarboxamide; N6-[1-(thiophen-2-yl)-2-methylpropyl]adenosine-5'-N-ethylcarboxamide; N6-[(R)-1-(5'-chlorothien-2yl)-2-butyl]carbocyclicadenosine-5'-N-ethylcarboxamide;N6-[2-(4'-methyl-2'-thiazolyl)ethyl]adenosine;N6-[4'-phenyl-2'-thiazolyl)methyl]adenosine;(-)-]2S-[2α,3α-dimethylmethylenedioxy-4-β-[N6-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino]-9-adenyl]cyclopentane]-1-β-N-ethylcarboxamide;(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide;(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-N.sup.1-oxide; [1S-[1α, 2β,3β,4α(S*)]]-4-[7-[[2-(5-chloro-2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide;[1S-[1α,2β,3β,4α]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide;[1S-[1α,2β,3β,4α]]-4-[7-[[2-(2-thienyl)-1-isopropylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide;[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide;[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N- ethyl-2,3-dihydroxycyclopentane-carboxamide;[1S-[1α,2β,3β,4α]]-4-[7-[[2-(5-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide;(2S)-2α,3α-bis-methoxycarbonyloxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide;(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamideethoxymethylene acetal;(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-2,3-carbonate;(2S)-2α,3α-bis-methylcarbamoyloxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide;(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-2,3-thiocarbonate; N⁶-[2-(3-chloro-2-thienyl)-(1R)-1-methylethyl]-2'-O-methyladenosine; N⁶-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]-2'-O-methyladenosine; andN⁶ -[trans-5-(2-thienyl)cyclohex-1-en-4-yl]-2'-O-methyladenosine.

A preferred class of compounds of the invention is described by FormulaI wherein R' and R" are H.

Another preferred class of compounds of the invention are the5'-N-alkylcarboxamide derivatives of the N6-heterocyclic-substitutedcarbocyclic adenosines, in other words, the compounds of Formula I,wherein K is N, Q is CH₂ and T is R₁ R₂ N--C═O, or pharmaceuticallyacceptable salts thereof.

Still another preferred class of compounds of the invention are the5'-N-alkylcarboxamide derivatives of theN6-heterocyclic-substituted-N'-1-deazaaristeromycins, i.e., the4-[7-[heterocyclylamino]-3H-imidazo[4,5-b]pyridin-3-yl]-alkyl-2,3-dihydroxycyclopentanecarboxamides,in other words, the compounds of Formula I, wherein K is CH, Q is CH₂,and T is R₁ R₂ N--C═O, or pharmaceutically acceptable salts thereof.

The most preferred class of compounds of the invention comprise thecompounds of Formula I characterized by the presence of a chiral centeralpha to the N6 atom of the purine or 1-deazapurine ring, while aspecial embodiment of this class includes compounds characterized by achiral ethyl group attached to the carbon atom alpha to the N6-nitrogen.A particularly preferred class of compounds are characterized by anN6-[1-loweralkyl-2-(3-halothien-2-yl)ethyl]substituent group.

Most preferred embodiments of the invention comprise the compounds(-)-[2S-[2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-1-(R)-methylethyl]-amino]-9-adenyl]cyclopentane-1β-ethylcarboxamide,(-)-[2S-[2α,3α-dihydroxy-4β-[N6-[1-(R)-ethyl-2-(3-chloro-2-thienyl)ethyl]amino]-9-adenyl]cyclopentane-1β-ethylcarboxamide,[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(5-chloro-2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,and pharmaceutically acceptable salts thereof.

Compounds of this invention may be prepared by known methods or inaccordance with the reaction sequences described below. The startingmaterials used in the preparation of compounds of the invention areknown or commercially available, or can be prepared by known methods orby specific reaction schemes described herein.

Compounds of Formula I, wherein K is N, Q is 0 and T is R₃ O--CH₂, maybe prepared by reacting commercially-available 6-chloropurine ribosidewith various heterocyclic amines as exemplified below.

Compounds of Formula I, wherein K is N, Q is O and T is R₁ R₂ N--C═O aresimilarly prepared starting with the product of Reaction Scheme A. Inthis reaction, 6-chloropurine riboside, with the 2'- and 3'- hydroxylgroups of the ribose ring protected, is treated with an oxidant, forexample a Jones reagent, and the product acid treated with eitherdicyclohexlcarbodiimide (DCC) or BOP-Cl in the presence of a selectedamine, to yield the 5'-alkylcarboxamide derivative. ##STR7##

Suitable starting materials for compounds of Formula I wherein K is N, Qis CH₂ and T is R₁ R₂ N--C═O, may be prepared as described by Chen etal., Tetrahedron Letters 30: 5543-46 (1989). Alternatively, ReactionScheme B may be used to prepare such starting materials. In carrying outReaction Scheme B, the 4-ethylcarboxamide derivative of2,3-dihydroxycyclopentylamine, prepared as described by Chen et al., isreacted with 3-amino-2,4-dichloropyrimidine. The product of this initialreaction is then heated with an aldehydylamidine acetate, for exampleformamidine acetate in dioxane and methoxyethanol, for a time sufficientto effect ring closure (from about 30 min to about 4 hours), therebyyielding a product which may be conveniently reacted with variousheterocyclic amines in the manner described below, to give the compoundsof the invention. The order of reaction is not critical. For example,the intermediate formed in Reaction Scheme B could be reacted with aheterocyclic amine, followed by ring closure to yield the desired finalproduct. ##STR8##

Various heterocyclic amines, useful in forming the compounds of thisinvention, may be prepared by one or more of the reactions shown inReaction Schemes C-J and preparative Examples B through G, and 50through 74, hereinbelow (Het=heterocyclic group; Halo=halogen; R=e.g. Hor lower alkyl; R_(a) and Y are as previously described). ##STR9##

The reaction sequence of Scheme I above is described in U.S. Pat. No.4,321,398, with pertinent information incorporated herein by reference.

EXAMPLE B Preparation of 1-(thiophen-3-yl)ethylamine

3-Thiophencarboxaldehyde (1 mmole), nitromethane (1.5 mmole) andbeta-alanine (0.1 mmole) in butanol for 6 hours to give 3-nitrovinylenethiophene, which is reduced with lithium aluminum hydride(2.5 mmole) to yield the desired product amine.

3-Substituted thienylalkylamines are prepared by substituting3-substituted thiophenes, such as 3-chlorothiophene, for the thiophenestarting materials in Example B above.

EXAMPLE C Preparation of trans-2-(thiophen-2-yl)cyclohex-4-enylamine

A mixture of 1,3-butadiene (5 ml) and 2-nitrovinylenethiophene (7 g) intoluene is heated at 140° C. overnight in a sealed tube. The resultingnitrocyclohexene is hydrogenated (˜35 psi H₂) (5% Pd/C MeOH) and treatedwith lithium aluminum hydride (2.5 g). The racemictrans-2-(thiophen-2-yl)-cyclohexylamine is obtained with a standardworkup.

EXAMPLE D General Preparation of 2-substituted Thiazole Amines

Benzoyl chloride and aminoethylcyanide are reacted to giveN-benzoylaminoethylcyanine, which is reacted with hydrogen sulfide inammonia to yield the thioamide, which is reacted with an appropriateα-halo ketone to yield the desired thiazole. Treatment with 5Nhydrochloric acid removes the protecting benzoyl group to give thedesired amine product.

EXAMPLE E General Preparation of 4-Substituted Thiazolyl Amines

A preferred synthesis for 2-(2'-methyl-4'-thiazolyl)ethylamine is byreacting thioacetamide with ethyl monobromoacetoacetate to give athiazole ester which is reduced preferably with sodium borohydride toyield the alcohol which is converted to the amine. A preferred means tothe amine comprises treatment with (i) diethylazodicarboxylate,triphenylphospine and phthalimide and (2) hydrazine hydrate.

The preparation of 4-substituted thiazole amines may also be carried outby using the foregoing reaction scheme by reacting a substitutedthioamide and ethylmonobromoacetoacetate. Conversion of the resultingthiazolyl ester to the amide is effected with aqueous ammonia and theamine is formed by reduction with borane. An exemplary preparation of2-(1,1-dimethyl-1'-thiophenyl)ethylamine is described in U.S. Pat. No.4,321,398.

Diastereomeric mixtures of compounds or intermediates obtained inReaction Schemes A-I above may be separated into single racemic oroptically active enantiomers by methods known in the art; for example,by chromatography, fractional distillation or fractional crystallizationof d- or l-(tartarate, dibenzoyltartarate, mandelate orcamphorsulfonate) salts.

EXAMPLE F Preparation of (+) and (-)trans-2-(thiophen-2-yl)cyclohex-4-enylamine

(S)-(+)-Mandelic acid (0.55 eq) is added to an isopropanol solution ofthe racemic amine (3.4 g) prepared in Example C. The precipitate isrecrystallized from isopropanol to provide 1.78 g of the salt ([α]_(D)RT=+4.13 (C=1.3, MeOH)). The amines are isolated by extracting theneutralized salts (sat. NaHCO₃) with CH₂ Cl₂, drying (Na₂ SO₄) andconcentrating to provide the free amines partially resolved.

Approximately 1 g of the levorotatory amine ([α]_(D) RT=-25.8 (c=1.54,MeOH)) is treated with 2 g of l-(-)-dibenzoyl tartaric acid in methanoland the resulting salt is worked up to provide 0.64 g of thelevorotatory amine ([α]_(D) RT=-28.8 (c=1.65, MeOH)). High-field NMRanalysis of the MPTA amide of the levorotatory amine revealed >96%enantiomeric excess.

Approximately 1.6 g of the enriched dextrorotatory amine mixture istreated with 3.2 g of d(+)-dibenzoyl tartaric acid in methanol. Afterworkup, 0.87 g of the dextrorotatory amine is obtained ([α]_(D) RT=+25.8(c=1.67, MeOH)).

The N6-heterocyclic-substituted adenosines and carbocyclic adenosines ofthe invention may be formed by reacting 6-chloropurine riboside or theproducts of Reactions Scheme A or B with various heterocyclic amines,according to the synthetic route shown below in Reaction Scheme J,wherein K, P, Q and T are as previously defined. ##STR10##

The N6-heterocyclic-substituted-N'alkyl-deazaaristeromycins of theinvention may be prepared as shown in Reaction Scheme K. ##STR11##

Compounds of the present invention which may act as pro-drugs includethose compounds wherein the hydroxyl groups on the ribose orcyclopentane ring are substituted with groups R' and R" as defined abovefor Formula I.

These may be prepared by known methods and are exemplified by thepreparations shown in Reaction Scheme L, below. ##STR12##

Treatment of the dihydroxy compounds with a chloroformate ester in thepresence of an organic base, for example triethylamine, will give thecorresponding bis-carbonate. The alkoxymethylene acetal may be preparedby treatment with the corresponding orthoester in the presence of acatalytic amount of p-toluenesulfonic acid. The carbonate is availableby treatment with 1,1'-carbonyldiimidazole and the thiocarbonate bytreatment with thiocarbonyldiimidizole. The alkyl and dialkylcarbamoylderivatives may be prepared by treatment with the corresponding alkylisocyanate or dialkyl carbamoyl chloride in the presence of an organicbase respectively.

Compounds of the present invention wherein K is N→O, i.e. the N-oxides,may be prepared by oxidation of the corresponding adenosine orcarbocyclic adenosine by known methods, for example by treatment withhydrogen peroxide in acetic acid.

The 2'-O-alkyl derivatives may be prepared by known methods, for exampleby reaction of the appropriate heterocyclyl amine with6-chloro-9-(2'-O-methyl-β-D-ribofuranosyl)-9H-purine.

Functional groups of starting compounds and intermediates that are usedto prepare the compounds of the invention may be protected by commonprotecting groups known in the art. Conventional protecting groups foramino and hydroxyl functional groups are described, for example, in T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York(1984).

Hydroxyl groups may be protected as esters, such as acyl derivatives, orin the form of ethers. Hydroxyl groups on adjacent carbon atoms mayadvantageously be protected in the form of ketals or acetals. Inpractice, the adjacent 2' and 3' hydroxyl groups of the startingcompounds in Reaction Schemes A and B are conveniently protected byforming the 240 ,3' isopropylidene derivatives. The free hydroxyls maybe restored by acid hydrolysis, for example, or other solvolysis orhydrogenolysis reactions commonly used in organic chemistry.

Following synthesis, compounds of the invention are typically purifiedby medium pressure liquid chromatography (MPLC), on a chromatotron,radially accelerated thin layer chromatography, flash chromatography orcolumn chromatography through a silica gel or Florsil matrix, followedby crystallization. For compounds of Formula I wherein K is N, Q is Oand T is R₃ O--CH₂, typical solvent systems include chloroform:methanol,ethyl acetate:hexane, and methylene chloride:methanol. Eluates may becrystallized from methanol, ethanol, ethyl acetate, hexane orchloroform.

For compounds of Formula I, wherein K is N, Q is O and T is R₁ R₂N--C═O, typical solvent systems include chloroform:methanol. Eluates maybe crystallized from 50-100% ethanol (aqueous).

For compounds of Formula I, wherein Q is CH₂, K is N or CH, and T is R₁R₂ N--C═O, typical solvent systems include methylene chloride:methanol.Eluates may be crystallized from ethyl acetate with or without methanol,ethanol or hexane.

Compounds requiring neutralization may be neutralized with a mild basesuch as sodium bicarbonate, followed by washing with methylene chlorideand brine. Products which are purified as oils are sometimes trituratedwith hexane/ethanol prior to final crystallization.

A further aspect of the present invention relates to an improved methodfor preparing a substantially optically pure2-substituted-2-amino-1-(heteroar-2' or 3-yl) ethane derivative.2-(Heteroaryl)ethylamines and alkyl and phenyl derivatives thereof havebeen prepared by a variety of means including reduction of2-β-nitrovinylheteroaryl compounds prepared from theheteroarylformaldehydes (see, e.g., W. Foye and S. Tovivich, J. Pharm.Scien. 68 (5), 591 (1979), S. Conde, et al., J. Med. Chem. 21 (9), 978(1978), M. Dressier and M. Joullie, J. Het. Chem. 7, 1257 (1970));reduction of cyanomethylheteroaryl compounds (see, e.g., B. Crowe and F.Nord, J. Org. Chem. 15, 81 (1950), J. McFarland and H. Howes, J. Med.Chem. 12, 1079 (1969)); Hoffman degradation reaction of2-(2-thienyl)propyl amide (see, e.g., G. Barger and A. Easson, J. Chem.Soc. 1938, 2100); and amination of2-(2-thienyl)ethylparatoluenesulfonates, U.S. Pat. No. 4,128,561.

The present method comprises reacting a chiral 2-substituted ethyleneoxide derivative with a 2' or 3-yl anion of a heteroaryl compound, andconverting, by stereospecific means, the hydroxy group formed in saidreaction to an amino group. The method of the present invention is shownin Reaction Scheme M below. ##STR13##

Where Sub represents a substituent group on said chiral ethylene oxideand Het represents a heterocyclic group.

An advantage of the method of the present invention over methods ofpreparation of 2-substituted-2-amino-l-(heteroar-2- or 3-yl) ethanederivatives known in the art is that of preparation of a substantiallyoptically pure derivative directly as contrasted with that of a racemicmixture which must then be resolved by other methods to yield theoptically pure isomers.

A preferred class of the method of the present invention is that inwhich the heteroar-2- or 3-yl group is a substituted or unsubstitutedthien-2- or 3-yl or a substituted or unsubstituted benzothiophen-2- or3-yl group.

A more preferred class of the method of the present invention is that inwhich said anion is formed by reacting a substituted or unsubstitutedthiophene or benzothiophene having a hydrogen substituent in the 2- or3- position with an organometallic base in an aprotic organic solvent.

Another more preferred class of the method of the present invention isthat in which said chiral 2-substituted ethylene oxide is substituted inthe 2-position by a group selected from the group consisting of alkyl,aryl, trihalomethyl, and benzyloxy.

A most preferred class of the method of the present invention is that inwhich said organometallic base is an alkyllithium or lithiumdiisopropylamide, said aprotic organic solvent is tetrahydrofuran,ether, hexane, or a mixture of those solvents, and said chiral2-substituted ethylene oxide is a 2-alkyl ethylene oxide derivative.

Means for stereospecifically converting a hydroxy group to an aminogroup are well known in the art (see, e.g., Mitsunobu, Synthesis 1981(1), 1).

It should be apparent that the (R)- or(S)-2-substituted-2-hydroxy-1-heteroarylethane derivative may be formeddirectly as described above by use of the corresponding (S)- or(R)-2-substituted ethylene oxide derivative as the starting material or,if desired or necessary, a resulting (R) or(S)-2-substituted-2-hydroxy-1-heteroarylethane could be converted to thecorresponding (S) or (R)-2-substituted-2-hydroxy-1-heteroarylethanederivative, respectively, by means, well known in the art, for invertingthe configuration at the hydroxy group (see, e.g., Mitsunobu, Synthesis1981 (1), 1).

A specific embodiment of the method of the present invention is that inwhich: (a) a substituted or unsubstituted thiophene or benzothiophenehaving a hydrogen substituent in the 2- or 3- position is treated withbutyllithium in a mixture of tetrahydrofuran and hexanes at a reducedtemperature, for example about -30° C., for a time sufficient to formthe anion of said thiophene or benzothiophene; (b) thereafter an (S) or(R) 2-alkyl ethylene oxide is added and the mixture held at a highertemperature, for example about 0° C., for a time sufficient to form thecorresponding (R) or (S) 2-alkyl-2-hydroxy-1-thienyl or benzothiophenylethane derivative; and (c) thereafter converting, by a stereospecificmeans, the hydroxy group of said ethane derivative to an amino group.

The method of the present invention is further illustrated and explainedby Examples 50 through 74 hereinbelow.

Examples 1-3 describe the preparation of precursor compounds used in thepreparation of compounds of the present invention which are describedbelow.

EXAMPLE 1 Preparation of6-Chloro-2',3'-dimethylmethylenedioxy-N-5'-ethyl carboxamido adenosine

Step 1: 2',3'-dimethylmethylene derivative of 6-chloropurine riboside

6-Chloropurine riboside (31.5 g), triethylorthoformate (73 ml) and TsOH(19.8 g) are stirred in 600 ml acetone for 2 hours at RT. The solutionwas reaction mixture is concentrated in vacuo, combined with ethylacetate and washed with saturated NaHCO₃ solution, and brine, dried (Na₂SO₄) and concentrated to yield the 2',3'-dimethylmethylene derivative of6-chloropurine riboside as a white solid.

Step 2: 6-Chloro-2',3' dimethylmethylenedioxy adenosine-5'-carboxylicacid

The product of Step 1 (10 g) is subjected to a Jones oxidation, the acidextracted from ethyl acetate with 2.5% NaOH solution, and the aqueousportion washed with ethyl acetate and acidified with concentrated HCland extracted with ethyl acetate. The organic layer is washed with H₂ Oand brine, dried (Na₂ SO₄), filtered and concentrated in vacuo todryness, yielding the desired 5'-carboxylic acid.

Step 3: 6-Chloro-2',3'-dimethylmethylenedioxy-N-5'ethyl carboxamidoadenosine

The product from Step 2 (5.7 g) is stirred with BOP-Cl(Bis-(2-oxo-3-oxazoladinyl) phosphinic chloride) (4.26 g) andtriethylamine (2.33 ml) in 100 ml methylene chloride for 20 min at RT.Ethylamine (3.46 g) is stirred into the solution which is stirred for 2hours at RT. The organic portion is washed with diluted HCl solution,dilute NaOH, H₂ O, brine and dried (Na₂ SO₄) to yield the final productas a foam.

EXAMPLE 2 Preparation of(+)-2S-[2α,3α-dimethylmethylenedioxy]-4β-[6-chloro-9-adenyl]cyclopentane-1-β-N-ethylcarboxamide

Step 1: 5,6-Dimethylenedioxy-2-azabicyclo[2.2.1 ]heptan-3-one

5,6-Dihydroxy-2-azabicyclo[2.2.1]heptan-3-one (23.5 g), (Aldrich) orprepared according to the procedure of Cermak and Vince, Nucleic AcidChemistry, Improved and New Synthetic Procedures, Methods andTechniques, Part Three, page 26 (J. Wiley 1986), is dissolved in acetone(150 ml) containing 2,2-dimethoxypropane, (185 ml) and p-toluenesulfonicacid (5.25 g), and the mixture is refluxed for 10 min, cooled, treatedwith NaHCO₃ (9.3 g) and concentrated in vacuo. The residue is dissolvedin CH₂ Cl₂, washed with brine, dried over MgSO₄ and the solventevaporated to yield a oil. The oil is chromatographed SiO₂ (4:1, ethylacetate hexane) to give 17.0 g (63%) of a tan white solid. (mp 153°-154°C.).

Step 2:(+)-4β-amino-2α,3α-dimethylenedioxycyclopentane-1β-N-ethylcarboxamide

(A) 5,6-Dimethylenedioxy-2-azabicyclo[2.2.1 ]heptan-3-one (5 g),prepared in Step 1, is treated with ethylamine (15 ml) at 140° C. forabout 7 hours. The resulting product is purified by flash chromatography(CH₂ Cl₂ /CH₃ OH/N,N-dimethyl ethylamine, (90/7/3) to yield(±)4β-amino-2α,3α-dimethylenedioxy cyclopentane-1β-ethylcarboxamide (5.8g).

(B) Treatment of the racemic amine (13.1 g), prepared as described inpart A, with D-dibenzoyltartaric acid (21.6 g) affords 15.1 g of anenantiomerically pure salt, [α]_(D) RT=+70.1 (C. 1.77, CH₃ OH). The saltis dissolved in 10% aqueous NaOH and the aqueous phase is extracted withethyl acetate. The combined organic layers are washed with brine, driedover MgSO₄ and the solvent removed to afford the optically purecompound. [α]_(D) RT=+31.4[C. 1.40, MeOH]

Step 3:4-β-(3-amino-4-chloro-2-pyrimidinylamino)-2,3-dimethylenedioxycyclopentane-1β-N-ethyl-carboxamide

Condensation of (+)4β-amino-2α,3α-dimethylenedioxycyclopentane-1β-N-ethyl carboxamide (2.10g), prepared in Step 2, part B, with 3-amino-2,4-dichloropyridine (1.5g) in n-butanol (70 ml) containing triethylamine (3 mi) for about 14hours at reflux followed by removal of solvent in vacuo affords an oilwhich is dissolved in ethyl acetate and washed with aqueous NaHCO₃. Theorganic extract is dried over Na₂ SO₄ and concentrated in vacuo to yieldthe optically pure compound. [α]_(D) RT=+15.8(C.41.48, CH₃ OH)

Step 4: (+)-4β-(3-amino-4-chloro-2-pyrimidinylamino)-2α,3α-dimethylenedioxycyclopentane (2.10 g), formamdine acetate (1.85 g) inmethoxyethanol (2 ml) and dioxane (80 ml) are stirred at 70° C. forabout 3 hours. The mixture is cooled to room temperature and the solventremoved in vacuo. The residue is dissolved in ethyl acetate which iswashed with aqueous NaHCO₃ and brine, the organic extract is dried overNa₂ SO₄, concentrated in vacuo and purified by flash columnchromatography (methylene chloride/methanol 95:5) to yield pure(+)-[2α,3α-dimethylmethylenedioxy]-4β-[6-chloro-9-adenyl]cyclopentane-1β-N-ethylcarboxamide (1.45 g).

Alternatively, optically pure 2α,3α-diprotecteddioxy-4β-6-substituted-9-adenyl-cyclopentane-1β-N-ethyl carboxamidederivatives can be prepared by the reaction scheme exemplified inExample 3.

EXAMPLE 3 Preparation of 2S-[2α,3α-cyclohexylidenedioxyl]-4β-[N6-(2-thienethan-2yl)-9-adenyl]cyclopentane-1β-N-ethylcarboxamide

Step 1: 4β-ethylene-2α,3α-[cyclohexylidenedioxy]cyclopentanone

(-)-2α,3α-[Cyclohexylidenedioxy]-4-cyclopentanone, (2.95 g), preparedfollowing the procedure of Borchardt et. al. J. Org. Chem. 1987, 52,5457, is added as a solution in THF (5 ml) to a mixture of vinylmagnesium bromide (15.2 mmol) and Cul (15.2 mmol) in THF (100 ml). Thismixture is maintained at -78° C. under an inert atmosphere for about 2hours, warmed to 0° C. and quenched with saturated aqueous NH₄ Cl. Theorganic phase is washed with brine, dried over MgSO₄ and concentrated invacuo to leave a yellow oil, which is purified by flash chromatography(methylene chloride, 100%) to yield 2.9 g of the desired compound as anoil.

Step 2: 4β-ethylene-1-β-hydroxy-2α,3α-[cyclohexylidenedioxy]cyclopentane

3.95 ml of a 1M solution of diisobutyl aluminum hydride inTetrahydrofuran is added to a solution of THF(75 ml) and ketone preparedin Step 1 (0.73 g), which is cooled to -78° C. The mixture is warmed to-40° C. for about 2.5 hours, treated with 2N NaOH (5 ml), warmed to roomtemperature and stirred for about 1.5 hours. The aqueous phase isextracted with diethyl ether, and the combined organic phases are washedwith brine, dried over MgSO₄ and concentrated in vacuo to a yellow oilwhich is purified by flash column chromatography (methylenechloride/methanol, 95:5) to yield 0.65 g of pure product as a viscousoil.

Step 3:4β-ethylene-1β-trifluoromethanesulfonyl-2,3-[cyclohexylidenedioxy]cyclopentane

A solution of4β-ethylene-1β-ethylene-1β-hydroxy-2α,3α-[cyclohexylidenedioxy]-cyclopentane(0.65 g) in methylene chloride (5 ml) and pyridine (0.24 ml) is added toa stirred solution of trifluoromethyl sulfonyl anhydride (0.49 ml) inmethylene chloride (25 ml) at 0° C. under argon. After about 20 min.,brine is added to the reaction mixture, the organic phase is dried overNa₂ SO₄ and the solvent is removed in vacuo to yield the desired productas an orange oil, which is used without further purification.

Step 4:1-β-ethylene-[2α,3α-cyclohexylidenedioxy]-4-β-[N6-(2-thienylethane-2-yl)9-adenyl]cyclopentane

A solution of N6-thiophenylethyl purine (2.13 g), NaH (50% oildispersion, 0.35 g) and 18-crown-6 (0.15 g) in DMF (60 ml) is added to asolution of4β-ethylene-1β-trifluoromethylsulfonyl-2α,3α-[cyclohexylidenedioxy]cyclopentane,prepared in step 4, in DMF (2 ml) at 0° C. The mixture is stirred at 0°C. for about 8 hours, quenched with saturated NH₄ Cl, the solventremoved in vacuo, and the residue combined with ethyl acetate (100 ml)and brine. The organic layer is dried over MgSO₄, and concentrated invacuo, and the crude product purified by flash chromatography (methylenechloride/methanol (99:1)) to yield 0.85 g of pure product.

Step 5:2S[2α,3α-cyclohexylidenedioxy]-4β-[N6-(2-thienylethan-2-yl)-9-adenyl]cyclopentane-1-β-N-ethylcarboxamide

A solution of1β-ethylene-[2α,3α-cyclohexylidenedioxy]-4-β-[N6-(2-thienylethane-2-yl)-9-adenyl]cyclopentane(0.32 g) in 2 ml of benzene is added to a benzene solution of potassiumpermanganate (0.29 g) and 18-crown-6 (0.016 g) at 0° C. The reactionmixture is maintained at room temperature for about 6 hours, 5% aqueousNaOH (15 ml) added and the aqueous phase filtered through Celite®, andacidified to pH 5 with 1N HCl, and extracted with ethyl acetate. Theorganic extracts is dried over MgSO₄ and concentrated in vacuo to yield0.1 g of]2α,3α-cyclohexylidenedioxy]-4β-]N6-(2-thienylethan-2-yl)-9-adenyl]cyclopentane-1-β-carboxylateas a yellow oil which is dissolved in methylene chloride (4 ml)containing dicyclohexyl carbodimide (DCC) (0.044 g). Ethylamine (0.4 ml)is added to the mixture which is allowed to stir at room temperature forabout 18 hours, the solvent removed in vacuo and the crude productpurified by flash chromatography (methylene chloride/methanol 98:2) toyield 0.077 g of pure product.

EXAMPLE 4 Preparation of N6-[trans-2-(thiophen-2-yl)cyclohex-4-en-yladenosine

Trans-2-(2'-thiophenyl)-cyclohex-4-enylamine (0.3 g) prepared accordingto method described in Example C, above, 6-chloropurine riboside (0.28g) and triethylamine (0.27 ml) in 20 ml ethanol are heated to refluxovernight under argon. The reaction mixture is cooled to RT, the solventremoved, and the residue purified by MPLC (chloroform:methanol; 95:5),followed by drying in vacuo at approximately 80° C., to yield the finalproduct as a solid, M.P. 105°-110° C.; elemental analysis, C₂₀ H₂₃ N₅ O₄S.

EXAMPLE 5 Preparation ofN6-[trans-2-(thiophen-2-yl)cyclohex-4-en-1-yl]adenosine-5'-N-ethylcarboxamide

Step 1: (+)Trans-2-(thiophen-2-yl)cyclohex-4-enylamine and the2',3'-dimethylmethylenedioxy derivative of 6-Cl-NECA are reacted underthe conditions described in Example 4, to yield the2',3'-dimethylmethylenedioxy derivative of the final product.

Step 2: The 2',3'-dimethylmethylenedioxy derivative of the desiredproduct is mixed with trifluoroacetic acid/ water (90/110) for 30 min atRT, is neutralized by slowly pouring the mixture into a saturated sodiumbicarbonate solution, and is extracted with methylene chloride. Theaqueous layer is extracted with methylene chloride and the organiclayers combined, washed with brine, dried over magnesium sulfate andfiltered, and the filtered clear solution evaporated. The residue ispurified by flash chromatography (methylene chloride:methanol 9:1) toyield, upon drying in vacuo, the final product as a white glassy foam,M.P. 112°-117° C.; C₂₂ H₂₆ N₆ O₄ S.

EXAMPLE 6 Preparation of(-)-[2S-[2α,3α-dihydroxy-4-β-[N6-[2-(5-chloro-2-thienyl)-1R)-1-methylethyl]amino]-9-adenyl]cyclopentane]-1-β-N-ethylcarboxamide

Step 1:

Optically pure(+)-[2S-[2α,3α-dimethyl-methylenedioxy]-4-β-(6-chloro-9-adenyl)]cyclopentane-1-β-N-ethylcarboxamide,prepared as described in Example 2, and2'R-(5-chlorothien-2-yl)-2-propyl amine, [α]_(D) RT=-15.6(C. 3.7, CH₃OH), prepared as described in Example 4, are combined as described inExample 4 affording the 2,3-dimethylmethylenedioxy derivative of thefinal product. Step 2:

The dimethylmethylenedioxy derivative of step (1) is heated in 5 ml of50% aqueous formic acid to reflux for about 3hours. The cooled reactionmixture is evaporated, toluene added to the solid residue and thesolvent evaporated. The residue was dissolved in ethyl acetate, washedwith sodium bicarbonate solution and brine, dried, filtered, andevaporated to give, after oven drying overnight, a white solid product(0.240 g), M.P. 188°-4° C.; C₂₀ H₂₅ N₆ SO₃ Cl, [α]_(D) RT--86.49 (C.5.5, MeOH).

EXAMPLES 7-29, 31-34

Following the general procedures of Examples 1 to 6 above, the compoundsof the invention set forth in Table 1 were prepared. In Examples 7through 21, 31 and 32, the heterocyclic amine was reacted withcommercially available 6-chloropurine riboside; in Examples 22 and 23,the heterocyclic amine was reacted withN6-chloro-5'-N-ethylcarboxamidoadenosine; and in Examples 24 through31,33 and 34, the heterocyclic amine was reacted with either (±) or(+)-[2α,3α-dimethyl-methylenedioxy-4-β-(6-chloro-9-adenyl)-cyclopentane-1-β-N-ethylcarboxamide.

                                      TABLE I                                     __________________________________________________________________________    Example/                                                                      RXN Scheme                                                                           Amine                  Product          M.P./°C.                __________________________________________________________________________     7 (F)                                                                                ##STR14##             N.sup.6 -[trans-2-(thiophen-2-yl)- cyclohex-                                  1-yl]adenosine   165-170                         8 (F)                                                                                ##STR15##             N.sup.6 -[trans-2-(thiophen-3-yl)- cyclohex-                                  4-en-1-yl]adenosine                                                                             99-105                         9 (C)                                                                                ##STR16##             N.sup.6 -[2-(2'-aminobenzothia- zolyl)ethyl]                                  adenosine        218-219                        10 (C)                                                                                ##STR17##             N.sup.6 -[2-(2'-thiobenzothiazolyl)-                                          ethyl]adenosine  149-150                        11 (C)                                                                                ##STR18##             N.sup.6 -[2-(6'-ethoxyl-2'-thiobenzo-                                         thiazolylethyl]adenosine                                                                       154-155                        12 (H)                                                                                ##STR19##             N.sup.6 -[2-(4'-methylthiazol-5'-yl)-                                         ethyl]adenosine  202-203                        13 (G)                                                                                ##STR20##             N.sup.6 -[2-(2'-thiazolyl)ethyl]- adenosine                                                    181-183                        14 (H)                                                                                ##STR21##             N.sup.6 -[2-(2'-methyl-4'-thiazolyl)-                                         ethyl]adenosine  116-118                        15 (D)                                                                                ##STR22##             N.sup.6 -[(R)-1-methyl-2-(2'benzo- [b]-thiop                                  henyl)ethyl]adenosine.sup.a                                                                    133-134                        16 (G)                                                                                ##STR23##             N.sup.6 -[2-(4'-phenyl-2'-thiazolyl)-                                         ethyl]adenosine  124-126                        17 (I)                                                                                ##STR24##             N.sup.6 -[2-(1,1-dimethyl-2'- thiophenyl)eth                                  yl]adenosine     172-176                        18 (G)                                                                                ##STR25##             N.sup.6 -[2-(4'-methyl-2'-thiazolyl)-                                         methyl]adenosine 104-105                        19 (G)                                                                                ##STR26##             N.sup.6 -[4-phenyl-2-thiazolyl)- methyl]aden                                  osine            137-139                        20 (D)                                                                                ##STR27##             N.sup.6 -[1-(thiazol-2-yl)prop-2-yl]-                                         adenosine         99-106                        21 (D)                                                                                ##STR28##             N.sup.6 -[1-(5"-chlorthien-2"-yl)-2-                                          butyl]adenosine  135-136                        22 (F.sup.d)                                                                          ##STR29##             N.sup.6 -[trans-2-(thiophen-2-yl)- cyclohex-                                  4-en-1-yl]adenosine-  5-N-ethyl                                               carboxamide.sup.b                                                                              108-112                        23 (C.sup.d)                                                                          ##STR30##             N.sup.6 -[2-(2'-(aminobenzothia- zolyl)ethyl                                  ]adenosine-5-N- ethyl carboxamide                                                              123-124                        24 (H)                                                                                ##STR31##             (±)-N.sup.6 -[2-(4"-methyl-5"-thiazolyl)                                   thyl]carbocyclic adenosine-5'- N-ethyl                                        carboxamide      92-93                          25 (G)                                                                                ##STR32##             (±)-N.sup.6 -[2-(2"-thiazolyl)ethyl]-                                      carbocyclic adenosine-5'-N- ethyl                                             carboxamide      170                            26                                                                                    ##STR33##             (-)-N.sup.6 -[(thiopen-2"-yl)ethan-                                           2-yl]carbocyclic adenosine-5'- N-ethyl                                        carboxamide      185-187                        27 (D)                                                                                ##STR34##             (-)-N.sup.6 [(R)-1-(thiophen-2-yl)prop-                                       2-yl]carbocyclic adenosine-5'- N-ethyl                                        carboxamide.sup.c                                                                              85- 87                         28 (E)                                                                                ##STR35##             (±)-N.sup.6 -[1-(thiopen)-3-yl)ethan-                                      2-yl]carbocyclic adenosien-5'- N-ethyl                                        carboxamide      195-198                        29 (C)                                                                                ##STR36##             (±)-N.sup.6 -[2-(2'-aminobenzothia-                                        zolyl)ethyl]carbocyclic adenosine- 5'-N-ethy                                  l carboxamide    209-211                        31 (D)                                                                                ##STR37##             N.sup.6 -[1-ethyl-2-(3-chlorothien-2-                                         yl)ethyl]adenosine                                                                             137-139                        32 (D)                                                                                ##STR38##             N.sup.6 -[1-methyl-2-(3-chlorothien-                                          2-yl)ethyl]adenosine                                                                           137-139                        33 (D)                                                                                ##STR39##             (-)-[2S-[2α,3α-dihydroxy-4β                                  -[N.sup.6 - [2-(3-chloro-2-thienyl)-1(R,S)-                                   thylethyl]amino]-9-adenyl]cyclo- pentane-1.b                                  eta.-ethyl carboxamide                                                                         88-91                          34                                                                                    ##STR40##             (-)-[2S-[2α,3α-dihydroxy-4β                                  -[N.sup.6 - [2-(3-chloro-2-thienyl)-1(R)-                                     ethylethyl]amino]adenyl]cyclo- pentane-1.bet                                  a.-ethyl carboxamide                                                                           95-96                          __________________________________________________________________________     .sup.a optical rotation of alcohol precursor of amine: [α].sup.RT =     +14.9° (C.1.27, CH.sub.3 OH)                                           .sup.b optical rotation of amine: [α].sup.RT = +25.8°            (C.1.67, CH.sub.3 OH)                                                         .sup.c optical rotation: [α].sup.RT = -15.6° (C.3.04,            CH.sub.3 OH)                                                                  .sup.d amine reacted with 2',3'-isopropylidene derivative of N.sup.6          -chloro5'-N-ethylcarboxamide adenosine; deprotection according to             procedure of Example 11.                                                 

EXAMPLE 30 Preparation of(±)-N6-[1-(thiopheny-2-yl)ethan-2-yl]-N'-1-deazaaristeromycin-5'-N-ethylcarboxamide

Step 1: 2-chloro-3-nitro-4-[2-(2-thiophenyl)ethyl]aminopyridine

A mixture of 2,4-dichloro-3-nitropyridine (1.5 g), 2-aminoethylthiophene(1 g) and triethylamine (5 ml) is heated to reflux in EtOH (60 ml). Thereaction mixture is cooled, the solvent evaporated and the residuechromatographed on silica gel (10% hexane/CH₂ Cl₂) to yield the desiredaddition product.

Step 2: (±) 1β-N-ethylcarboxamide-2α,3α-isopropylidenedioxy-4β-[2-(3-nitro-4-[2-(2-thiophenyl)ethyl]aminopyridyl)amino]cyclopentane

A mixture of the thiophenylamino pyridine of step (1) (1.8 mmoles),(±)-1β-N-ethylcarboxamide-4β-amino-2α,3α-isopropylidenedioxycyclopentane (0.3 g) andtriethylamine (0.3 ml)is heated to reflux in nitromethane (15 ml) forabout 5 hours. The solvent is removed and the residue taken up inmethylene chloride, chromatographed on silica gel (2%methanol/chloroform) affording a solid product which is used as is inthe next step.

Step 3: (±) 1β-N-ethylcarboxamide-2α,3α-isopropylidenedioxy-4β-[2-(3-amino-4-[2-(2-thiophenyl)ethyl]aminopyridyl)amino]cyclopentane

A mixture of the nitro compound of step (2) (0.39 g), Pd/C (0.01 g) inethanol (7 ml) is stirred under a hydrogen atmosphere for about 5 hours.The catalyst is filtered and the filtrate, evaporated affording an oilwhich is purified on florisil (10% methanol/methylkene chloride) toyield the desired product as a solid.

Step 4:(±)-N6-[1-(thiopheny-2-yl)ethan-2-yl]-N'-1-deazaaristeromycin-5'-N-ethylcarboxamide

A mixture of the amino compound of step (3) (0.31 g) and formamidineacetate (0.72 g) in methoxyethanol (30 ml) is heated to reflux for about3 hours. The reaction mixture is cooled, the solvent evaporated andwater (5 ml) and formic acid(5 ml) added to the residue. The acidicmixture is heated to 50° C. for about 5 hours, after which the solventis removed and the residue chromatographed on silica gel (10%methanol/methylene chloride) yielding an oil which is recrystallizedfrom ethyl acetate to the desired product as a crystalline solid,M.P.=155°-156 ° C.

The optically pure compound is prepared using the + or - enantiomer ofthe cyclopentane amine in Step (2).

EXAMPLE 35 Preparation of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]ethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-N¹-oxide

A solution of2S-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide(0.25 g) and glacial acetic acid (20 ml) in 30% hydrogen peroxide (1 L)is stirred for 4 days at room temperature and the mixture concentratedin vacuo. The residue is purified by flash chromatography, eluting with20% methanol in ethyl acetate, followed by stirring with hot methanoland filtering to give the desired product, m.p.>240° C.

EXAMPLE 36 Preparation of[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(5-chloro-2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide

Step 1: Preparation of2-chloro-4-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-3-nitropyridin

Using essentially the procedure of Example 30, Step 1, and purifying thecrude product by flash chromatography, eluting with gradient of 10% to30% ethyl acetate in heptane, the desired product is prepared from2-(5-chloro-2-thienyl)-(1R)-1-methylethylamine.

Step 2: Preparation of(-)-1β-N-ethyl-2α,3α-isopropylidenedioxy-4β-[4-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-3-nitro-2-pyridyl]amino-cyclopentanecarboxamide

2-chloro-4-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-3-nitropyridine(0.68 g),(-)-1β-N-ethyl-2α,3α-isopropylidendioxy-4β-amino-cyclopentanecarboxamide(0.381 g), and triethylamine (0.85 ml) are combined in ethanol (50 ml)and the mixture heated at reflux for about 18 hours. The mixture isconcentrated in vacuo and the crude product purified by flashchromatography eluting with 0.5% methanol in methylene chloride to givethe desired product.

Step 3: Preparation of(-)-1β-N-ethyl-2α,3α,-isopropylidenedioxy-4β-[3-amino-4-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-2-pyridyl]amino-cyclopentanecarboxamide

(-)-1β-N-ethyl-2α,3α-isopropylidenedioxy-4β-[4-[4-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-3-nitro-2-pyridyl]amino-cyclopentanecarboxamide(0.90 g), and tin(II)chloride dihydrate (2.1 g) are combined in ethanol(20 ml) and the mixture heated at 70° C. for about 30 minutes. Themixture is poured over ice, made slightly alkaline with aqueous sodiumbicarbonate, and the aqueous extracted with ethyl acetate. The ethylacetate solution is dried over magnesium sulfate, filtered, andconcentrated in vacuo to give the desired product which is used, withoutfurther treatment, for the next step.

Step 4: Preparation of[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(5-chloro-2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide

Using essentially the procedure of Example 30, Step 4, the desiredproduct, m.p. 164°-165° C. is prepared from(-)-1β-N-ethyl-2α,3α-isopropylidenedioxy-4β-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-2-pyridyl]amino-cyclopentanecarboxamide.

Using essentially the procedures of Example 30, the compounds ofExamples are prepared from the appropriate starting materials.

EXAMPLE 37

[1S-[1α,2β,3β,4α]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,m.p. 79°-82° C.

EXAMPLE 38

[1S-[1α,2β,3β,4α]]-4-[7-[[2-(2-thienyl)-1-isopropylethyl]amino]-3H-imidazo[4,5-b]pyridin-2-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,m.p. 75°-85° C.

EXAMPLE 39

[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl[-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,m.p. 75°-78° C.

EXAMPLE 40

[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,m.p. 155°-6° C.

EXAMPLE 41 Preparation of[1S-[1α,2β,3β,4α]]-4-[7-[[2-(5-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide.

Using essentially the procedures of Example 36, the desired product,m.p. 77°-85° C., is prepared from2-(5-chloro-2-thienyl)-(1R)-1-ethylethylamine.

EXAMPLE 42 Preparation of(2S)-2α,3α-bis-methoxycarbonyloxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide

To a solution of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide(0.56 g) and triethylamine (0.5 ml) and 4-dimethylaminopyridine (1 mg)in tetrahydrofuran (25 ml) is added methyl chloroformate (0.21 ml) andthe solution stirred at room temperature for 1 hour. The mixture isdiluted with ethyl acetate, washed with brine, and the organic solutiondried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude product is recrystallized from hexane/ethyl acetate to give thedesired product, m.p. 74°-76° C.

Preparation of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-cyclopentane-1β-N-ethylcarboxamideethoxymethylene acetal

A solution of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide (0.14 g), triethylorthoformate (3 ml), andp-toluenesulfonic acid (1 mg) is heated at reflux for about 1 hour andthe solvent and the solvent then removed in vacuo. The residue isdissolved in ethyl acetate and the solution washed with brine, driedover sodium sulfate, filtered, concentrated in vacuo. The crude ispurified by flash chromatography, eluting with 5% methanol in methylenechloride, followed by recrystallization from hexane/ethyl acetate togive the desired product, m.p. 67°-70° C.

EXAMPLE 44 Preparation of (2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-2,3-carbonate

A solution of(2S)-2α,3α-dihydroxy-4α-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide(0.17 g) and 1,1'-carbonyldiimidazole (0.071 g) in benzene (5 ml) isrefluxed for 5 hours then stirred at 60° C. for about 18 hours. Thesolution is washed with brine, dried over magnesium sulfate, filteredand concentrated in vacuo. The residue is purified by flashchromatography, eluting with 5% methanol in methylene chloride, followedby crystallization from hexane/ethyl acetate to give the desiredproduct, m.p. 87°-89° C.

EXAMPLE 45 Preparation of(2S)-2α,3α-bis-methylcarbamoyloxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide

To a solution of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide(0.16 g) in tetrahydrofuran (5 ml) is added methyl isocyanate (-.05 ml)and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 drop). The solution is stirredat 50° C. for about 2.5 hours, cooled to room temperature, diluted withethyl acetate and washed with brine. The organic solution is washed withbrine, dried over magnesium sulfate and concentrated in vacuo. Theresidue is purified by flash chromatography, eluting with 5% methanol inmethylene chloride, followed by crystallization from hexane/ethylacetate to give the desired product, m.p. 97°-99° C.

EXAMPLE 46 Preparation of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide-2,3-thiocarbonate

A solution of(2S)-2α,3α-dihydroxy-4β-[N6-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]amino-9-adenyl]cyclopentane-1β-N-ethylcarboxamide(0.35 g) and thiocarbonyldiimidazole (0.134 g) in benzene (10 ml) isheated at 45° C. for about 2 hours. The solution is washed with brine,dried over magnesium sulfate, and concentrated in vacuo. The residue ispurified by flash chromatography, eluting with 5% methanol in hexane,followed by crystallization from hexane to give the desired product,m.p. 115°-117° C.

EXAMPLE 47 Preparation of N⁶-[2-(3-chloro-2-thienyl)-(1R)-1-methylethyl]-2'-O-methyladenosine

A solution of 6-chloro-9-(2'O-methylβ-D-ribofuranosyl)-9H-purine(prepared s in EP Publication No. 0378158) (0.28 g),2-(3-chloro-2-thienyl)-(1R)-1-methylethylamine (0.163 g), andtriethylamine (0.5 ml) in ethanol (30 ml) is refluxed for about 18hours, cooled and concentrated in vacuo. The residue is purified byflash chromatography, eluting with 10% methanol in methylene chloride,followed by crystallization from hexane/ethyl acetate, to give thedesired product, m.p. 75°-76° C.

EXAMPLE 48 Preparation of N⁶-[2-(5-chloro-2-thienyl)-(1R)-1-methylethyl]-2'-O-methyladenosine

Using essentially the procedure of Example 47, the desired product, m.p.84°-85° C., is prepared from2-(5-chloro-2-thienyl)-(1R)-1-methylethylamine.

EXAMPLE 49 Preparation ofN6-[trans-5-(2-thienyl)cyclohex-1-en-4-yl]-2'-O-methyladenosine

Using essentially the procedure of Example 47, the desired product, m.p.86°-89° C., is prepared from trans-2-(2-thienyl)cyclohex-4-enylamine.

EXAMPLE 50 Preparation of 1(R)-2-(5-chloro-2-thienyl)-1-methylethylamine

Step 1: Preparation of1(S)-2-(5-chloro-2-thienyl)-1-hydroxy-1-methylethane

A solution of 2-chlorothiophene (8.17 g) in tetrahydrofuran (80 ml) iscooled to -30° C. and 1.6M n-butyllithium in hexanes (43.0 ml) is addeddropwise. The mixture is stirred at -30° C. for about 1 hour,(S)-propylene oxide (4.00 g) is added, and the mixture is warmed to 0°C. and stirred at that temperature for about 3 hours. The reaction isquenched with saturated aqueous ammonium chloride solution, diluted withether, and the layers separated. The organic layer is washed with brine,dried over magnesium sulfate, and concentrated in vacuo to give thedesired product.

Step 2: Preparation of1(R)-2-(5-chloro-2-thienyl)-1-methyl-1-phthalimidoethane

To a solution of 1(S)-2-(5-chloro-2-thienyl)-1-hydroxy-1-methylethane(8.8 g), triphenylphosphine (13.1 g), and phthalimide (7.35 g) intetrahydrofuran (80 ml) is dropwise added diethyl azodicarboxylate (7.9ml). The solution is stirred for about 18 hours and the solvent removedin vacuo. The residue is purified by flash chromatography, eluting with20% hexanes in methylene chloride, to give the desired product.

Step 3: Preparation of 1(R)-2-(5-chloro-2-thienyl)-1-methylethylamine

1(R)-2-(5-chloro-2-thienyl)-1-methyl-1-phthalimidoethane (13.0 g) isdissolved in ethanol (75 ml) and hydrazine hydrate (2.5 ml) is added andthe mixture stirred at reflux for about 1 hour. The mixture is cooled toroom temperature, the solid removed by filtration, and the filtrateconcentrated in vacuo. The residue is dissolved in ethyl acetate andthis solution stirred with 5N aqueous hydrochloric acid. The layers areseparated and the aqueous adjusted to ph>10 with 10% sodium hydroxidesolution, then extracted with ethyl acetate. The organic solution iswashed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to give the desired product, [α]_(D) =-22.96°(c=11.5, methanol).

EXAMPLE 51 Preparation of 1(R)-2-(2-thienyl)-1-methylethylamine

Step 1: Preparation of 1(S)-2-(2-thienyl)-1-hydroxy-1-methylethane

Using essentially the procedure of Example 50, Step 1, the desiredproduct is prepared from thiophene.

Step 2: Preparation of 1(R)-2-(2-thienyl)-1-methyl! -l-phthalimidoethane

Using essentially the procedure of Example 50, Step 2, the desiredproduct is prepared from 1(S)-2-(2-thienyl)-1-hydroxy-1-methylethane.

Step 3: Preparation of 1(R)-2-(2-thienyl)-1-methylethylamine

Using essentially the procedure of Example 50, Step 3, the desiredproduct [α]_(D) =-15.6° (c=1, methanol) is prepared from1(R)-2-(2-thienyl)-1-methyl-1-phthalimidoethane.

EXAMPLE 52 Preparation of 1(S)-2-(5-chloro-2-thienyl)-1-methylethylamine

Step 1: Preparation of1(S)-2-(5-chloro-2-thienyl)-1-hydroxy-1-methylethane

To a stirred solution of1(S)-2-(5-chloro-2-thienyl)-1-hydroxy-1-methylethane (5.70 g) intetrahydrofuran (100 ml) is added triphenylphosphine (5.34 g) andbenzoic acid (2.49 g). Diethyl azodicarboxylate (3.22 ml) is addeddropwise and the mixture stirred at room temperature for about 18 hours.The solvent is removed in vacuo. The residue is purified by flashchromatography, eluting with 30% hexanes in methylene chloride, to give(R)-3-(5-chloro-2-thienyl)-2-propyl benzoate. The ester (3.91 g) isdissolved in dioxane (50 ml) and 20% aqueous sodium hydroxide (15 ml) isadded. The mixture is heated at 55° C. for 3 hours and concentrated invacuo. The residue is taken up in ethyl acetate (200 ml) and the organiclayer washed with brine, dried over magnesium sulfate, filtered,concentrated in vacuo to give the desired product.

Step 2: Preparation of 1(S)-2-(5-chloro-2-thienyl)-1-methylethylamine

Using essentially the procedure of Example 50, Steps 2 and 3, thedesired product,α_(D) =+21.71° (c=1.1, methanol) is prepared from1(S)-2-(5-chloro-2-thienyl)-1-methylethane.

Using essentially the procedures of Examples 50, 51, and 52, thefollowing compounds are prepared from appropriate starting materials.

EXAMPLE 53 1(R)-2-(benzothiophen-2-yl)-1-methylethylamine EXAMPLE 541(S)-2-(2-thienyl)-1-methylethylamine, α_(D) =15.5° (c=1, methanol)EXAMPLE 55 1(R)-2-(3-bromo-2-thienyl)-1-methylethylamine EXAMPLE 561(R)-2-[5-(2-pyridyl)-2-thienyl]-1-methylethylamine EXAMPLE 571(R)-2-[5-(2-thienyl)-2-thienyl]-1-methylethylamine EXAMPLE 581(R)-2-(5-phenyl-2-thienyl)-1-methylethylamine EXAMPLE 591(R)-2-(5-methoxy-2-thienyl)-1-methylethylamine EXAMPLE 601(R)-2-(5-methyl-2-thienyl)-1-methylethylamine EXAMPLE 611(R)-2-(5-bromo-2-thienyl)-1-methylethylamine EXAMPLE 621(R)-2-(5-iodo-2-thienyl)-1-methylethylamine EXAMPLE 631(R)-2-(5-methylthio-2-thienyl)-1-methylethylamine EXAMPLE 641(R)-2-(5-methylsulfonyl-2-thienyl)-1-methylethylamine EXAMPLE 651(R)-2-(5-ethyl-2-thienyl)-1-methylethylamine EXAMPLE 661(R)-2-(5-n-heptyl-2-thienyl)-1-methylethylamine EXAMPLE 671(R)-2-(3-methyl-2-thienyl)-1-methylethylamine EXAMPLE 681(R)-2-(4-methyl-2-thienyl)-1 -methylethylamine EXAMPLE 691(R)-2-(3-chloro-2-thienyl)-1-methylethylamine, [α]_(D) =-6.1° (c=1,methanol) EXAMPLE 70 1(R)-2-(4-chloro -2-thienyl)-1-methylethylamineEXAMPLE 71 1(R)-2-(3-chloro-5-phenyl-2-thienyl)-1-methylethylamineEXAMPLE 72 1(R)-2-(5-bromo-2-chloro-2-thienyl)-1-methylethylamineEXAMPLE 73 1(R)-2-(4-methyl-5-chloro-2-thienyl)-1-methylethylamineEXAMPLE 74 1(R)-2-(2,5-dichloro-3-thienyl)-1-methylethylamine

Compounds of the present invention are useful as anti-hypertensiveagents for the treatment of high blood pressure; they also increasecoronary blood flow, and, accordingly, are useful in the treatment ofmyocardial ischemia.

Compounds within the scope of this invention exhibit activity instandard A₁ /A₂ receptor binding assays for the determination ofadenosine receptor agonist activity in mammals. Exemplary testprocedures which are useful in determining the receptor binding affinityof compounds of the present invention are described below.

A. IN VITRO ADENOSINE RECEPTOR BINDING AFFINITY DETERMINATION

A₁ Receptor Binding Affinity was determined by competition assay basedon ligand displacement of ³ H-CHA (cyclohexyl adenosine) [ResearchBiochemicals Inc., Natick, Mass.] from receptor using a membranepreparation of whole rat brain, according to the procedure of R. F.Bruns et al., Mol. Pharmacol., 29: 331 (1986). Non-specific binding wasassessed in the presence of 1 mM theophylline.

A₂ receptor binding affinity was determined by a similar assaytechnique, based on ligand displacement of ³ H-CGS 21680, a known A₂receptor-specific adenosine agonist, from receptor, using membranes fromrat brain striatum. Non-specific binding was assessed in the presence of20 μm 2-chloroadenosine.

The assays were run in glass test tubes in duplicate at 25° C. Once themembranes were added, the tubes were vortexed and incubated at 25° C.for 60 minutes (A₁ assay) or 90 minutes (A₂ assay) on a rotary shaker.The assay tubes were vortexed halfway through the incubation and againnear the end. The assays were terminated by rapid filtration through 2.4cm GF/B filters using a Brandel Cell Harvestor. The test tubes werewashed three times with cold 50 mM tris-HCl (pH 7.7 or 7.4), withfiltration being completed within 15 seconds. The damp filter circleswere placed in glass scintillation vials filled with 10 ml of Aquasol II(New England Nuclear). The vials were allowed to shake overnight on arotary shaker and were placed into a liquid scintillation analyzer fortwo minute counts. IC₅₀ values for receptor binding, i.e. theconcentration at which a compound of the invention displaced theradiolabeled standard, were obtained using a curve-fitting computerprogram (RS/1, Bolt, Beranek and Newman, Boston, Mass.).

B. IN VITRO VASORELAXATION DETERMINATION IN ISOLATED SWINE CORONARYARTERIES

Swine coronary arteries were obtained from a local slaughter house,dissected carefully and cleaned of fat, blood and adhering tissue. Ringsapproximately 2-3 mm wide were cut and transferred to water-jacketedtissue baths (10 ml) filled with warm (37° C.), oxygenated (O₂ /CO₂:95%/5%) Krebs-Henseleit buffer and mounted on L-shaped hooks betweenstainless steel rods and a force transducer. The composition of theKrebs buffer is as follows (mM): NaCl, 118; KCl, 4.7; CaCl2, 2.5; MgSO₄,1.2; KH₂ PO₄, 1.2; NaHCO₃, 25.0; and glucose, 10.0. Rings wereequilibrated for 90 minutes with frequent buffer changes at a restingtension of 5 g. In order to assure optimal tension development, arterialrings were primed twice with 36 mM KCl and once with 10 μm. PGF2α,before being exposed to 3 μM PGF2α. When isometric tension had reached asteady state, accumulative doses of the adenosine agonists of theinvention (usually 1 mM to 100 μM, in half logs) were added to thebaths. Tension achieved with 3 μM PGF2α was considered equivalent to100%; all other values were expressed as a percentage of that maximum.IC₅₀ values for relaxation, i.e. the concentration at which a compoundof the invention caused a 50% reduction in tension, were determinedusing the above-mentioned linear curve fitting computer program.

C. IN VIVO MEAN ARTERIAL BLOOD PRESSURE (MAP) AND HEART RATE (HR)DETERMINATIONS IN NORMOTENSIVE ANESTHETIZED AND SPONTANEOUSLYHYPERTENSIVE RAT

1. Anesthetized Rat

Normotensive rats were anesthetized with sodium pentobarbital (50 mg/kg,i.p.) and placed on a heated surgical table. Cannulas were inserted intothe femoral artery and veined to allow the measurement of arterialpressure and to facilitate the intravenous administration of testcompounds. The animals was allowed to equilibrate for 10 minutes aftersurgery. Mean arterial pressure was continuously measured and recordedand heart rate was monitored using the arterial pressure pulse totrigger a cardiotachometer. After baseline parameters were establishedand recorded, increasing doses (1, 3, 10, 30, 100, 300 and 1000 μg/kg)of the compound of the invention to be tested were administeredintravenously. Maximal changes in the cardiovascular parameters wereobserved after each dose of the adenosine agonist. Only one compound wasadministered per rat. The potency of the compounds to lower heart rateand mean arterial pressure were assessed by determining the dose of theagent necessary to lower the heart rate or arterial pressure by 25%(ED₂₅).

2. Spontaneously Hypertensive Rat (SHR)

The oral antihypertensive activity of compounds of the invention wereexamined in conscious spontaneously hypertensive rats. The rats wereanesthetized with sodium pentabarbatol (50 mg/kg i.p.). A telemetrytransducer was implanted into the rats abdomen via midline incision. Thecannula of the transducer was inserted into the abdomenal aorta to allowdirect measurement of arterial pressure in the conscious SHR. Thetransducer was secured to the abdomenal wall. After recovery fromsurgery (minimum of seven days), the SHR were placed on a receiver plateand the transducer/transmitter was activated. Systolic, diastolic andmean arterial pressure and heart rate were recorded for 1.5 hours in theunrestrained conscious rat to establish a stable baseline. Each rat thenreceived a single dose of the compound of the invention to be tested, orvehicle, and changes in arterial pressure and heart rate were monitoredfor 20 hours and recorded.

Table II presents results of the biological activity determinations forexemplary compounds, and for the compound of Example 6, Step 1, withinthe scope of the invention.

                                      TABLE II                                    __________________________________________________________________________    Adenosine                                                                     Receptor          Vasorelaxation                                              Binding           in Swine                                                                              Blood Press/Heart Rate                              Activity/         Coronary                                                                              Anesthetized Rat                                    Ex.                                                                              IC50 (nM)      Artery/ MAP/ED25                                                                             HR/ED25                                                                             Dose SHR*                              No.                                                                              A.sub.1                                                                              A.sub.2 IC50 (μM)                                                                          (μg/kg)                                                                           (μg/kg)                                                                          (mg/kg)                                                                            MAP/%                                                                              HR/%                         __________________________________________________________________________     4 1.66   55      0.73    13     19    5    28 (D)                                                                             20 (D)                        5 4.26   91      0.068   --     --    --   --   --                            6 2.69   12.88   0.021   --     --    1    18 (D)                                                                             7 (l)                        6(1)                                                                             >1000  >1000   19.1    --     --    --   --                                 7 3.5    28      4       6      18    5    45 (D)                                                                             22 (D)                        8 5      138     --      10     23    --   --   --                            9 4      1000    11.9    5       4    --   --   --                           10 3.8    >1000   --      --     --    --   --   --                           11 7.4    >1000   --      --     --    --   --   --                           12 23     224     0.5     4      17    --   --   --                           13 41     191     0.24    3      >10   --   --   --                           14 79.4   >1000   --      --     --    --   --   --                           15 4.07   1000    2.45      1.5    1.4 --   --   --                           16 1.7    >1000   --      --     --    --   --   --                           17 67.6   5248    18.77   --     --    --   --   --                           18 166    52      0.46    2      >10   --   --   --                           19 36     1000    0.75    --     --    --   --   --                           20 3.98   158     --      --     --    --   --   --                           21 0.09   14.8    --      --     --    --   --   --                           22 2.69   29.5    0.1     --     --    --   --   --                           23 0.32   891     4.4     6       7    --   --   --                           24 >1000  >1000   --      6      >10   5    17 (D)                                                                             6 (l)                        25 1258.3 355     0.64    --     --    --   --   --                           26 87.1   63.1    0.082   4      >30     2.5                                                                              41 (D)                                                                             3 (l)                        27 5.01   29.5    0.043   --     --    1    27 (D)                                                                             1 (l)                        28 417    >1000   --      --     --    --   --   --                           29 35.48  >1000   22      16     31    5    18 (D)                                                                             12 (D)                       30 562    >1000   12.1    6      >10   --   --   --                           31 0.03   8.9     --      --     --    --   --   --                           32 0.049  45      --      --     --    --   --   --                           34 1.6    23      0.072   --     --    --   --   --                           35 1087   6351    3.3     --     --    --   --   --                           36 8.8    43.4    0.493   --     --    --   --   --                           37 16.2   110     0.45    --     --    --   --   --                           38 5.7    55.5    0.47    --     --    --   --   --                           39 3.98   46.8    --      --     --    --   --   --                           40 9.3    68.8    .283    --     --    --   --   --                           41 14.2   158     --      --     --    --   --   --                           42 >1000  >10000  2.44    --     --    --   --   --                           43 8428   >10000  7.83    --     --    --   --   --                           44 55     331     0.316   --     --    --   --   --                           45 6351   >10000  4.1     --     --    --   --   --                           46 13.5   81      3.52    --     --    --   --   --                           47 23     2818    5.7     --     --    --   --   --                           48 8.35   1445    --      --     --    --   --   --                           49 69     2884    9.81    --     --    --   --   --                           __________________________________________________________________________     *D signifies decrease; l signifies increase                              

The compounds of this invention can be normally administered orally orparenterally, in the treatment of patients suffering from hypertensionor myocardial ischemia. As used herein, the term "patients" includeshumans and other mammals.

The compounds of this invention, preferably in the form of a salt, maybe formulated for administration in any convenient way, and theinvention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Suitable carriers include diluents or fillers,sterile aqueous media and various non-toxic organic solvents. Thecompositions may be formulated in the form of tablets, capsules,lozenges, troches, hard candies, powders, aqueous suspensions, orsolutions, injectable solutions, elixirs, syrups and the like and maycontain one or more agents selected from the group including sweeteningagents, flavoring agents, coloring agents and preserving agents, inorder to provide a pharmaceutically acceptable preparation.

The particular carrier and the ratio of the adenosine agonists tocarrier are determined by the solubility and chemical properties of thecompounds, the particular mode of administration and standardpharmaceutical practice. For example, excipients such as lactose, sodiumcitrate, calcium carbonate and dicalcium phosphate and variousdisintegratants such as starch, alginic acid and certain complexsilicates, together with lubricating agents such as magnesium stearate,sodium lauryl sulphate and talc, can be used in producing tablets. For acapsule form, lactose and high molecular weight polyethylene glycols areamong the preferred pharmaceutically acceptable carriers. Where aqueoussuspensions for oral use are formulated, the carder can be emulsifyingor suspending agents. Diluents such as ethanol, propylene glycol,glycerin and chloroform and their combinations can be employed as wellas other materials.

For parenteral administration, solutions or suspensions of thesecompounds in sesame or peanut oil or aqueous propylene glycol solutions,as well as sterile aqueous solutions of the soluble pharmaceuticallyacceptable salts described herein can be employed. Solutions of thesalts of these compounds are especially suited for administration byintramuscular and subcutaneous injection. The aqueous solutions,including those of the salts dissolved in pure distilled water, aresuitable for administration by intravenous injection, provided thattheir pH is properly adjusted, and that they are suitably buffered, madeisotonic with sufficient saline or glucose and sterilized by heating orby microfiltration.

The dosage regimen used in carrying out the methods of this invention isthat which insures maximum therapeutic response until improvement isobtained and thereafter the minimum effective level which gives relief.Thus, in general, the dosages are those that are therapeuticallyeffective in lowering blood pressure in the treatment of hypertension,or in increasing coronary blood flow in the treatment of myocardialischemia. In general, the oral dose may be between about 0.1 and about100 (preferably in the range of 1 to 10 mg/kg), and the i.v. dose about0.01 to about 10 mg/kg (preferably in the range of 0.1 to 5 mg/kg),bearing in mind, of course, that in selecting the appropriate dosage inany specific case, consideration must be given to the patient's weight,general health, age and other factors which may influence response tothe drug.

The compounds of the invention may be administered as frequently as isnecessary to achieve and sustain the desired therapeutic response. Somepatients may respond quickly to a relatively large or small dose andrequire little or no maintenance dosage. On the other hand, otherpatients may require sustained dosing from about 1 to about 4 times aday depending on the physiological needs of the particular patient.Usually the drug may be administered orally about 1 to about 4 times perday. It is anticipated that many patients will require no more thanabout one to about two doses daily.

It is also anticipated that the present invention would be useful as aninjectable dosage form which may be administered in an emergency to apatient suffering from acute hypertension or myocardial ischemia. Suchtreatment may be followed by intravenous infusion of the active compoundand the amount of compound infused into such a patient should beeffective to achieve and maintain the desired therapeutic response.

What is claimed is:
 1. A compound of the formula ##STR41## wherein: K isCH;Q is CH₂ ; T is ##STR42## or R₃ O--CH₂ ; X is a straight or branchedchain alkylene, cycloalkylene or cycloalkenylene group; Y is NR₄, O orS;a=0 or 1; Z is of the formula ##STR43## Z₁ is N, CR₅, (CH)_(m) --CR₅or (CH)_(m) --N, m being 1 or 2; Z₂ is N, NR₆, O or S, n being 0 or 1;R₁, R₂, R₃, R₄, R₅ and R₆ are independently H, alkyl, aryl orheterocyclyl; R_(a) and R_(b) are independently H, OH, alkyl,hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino,alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, arylor heterocyclyl; and R' and R" are independently hydrogen, alkyl,aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or R' and R" togethermay form ##STR44## where r_(c) is hydrogen or alkyl, ##STR45## whereR_(d) and R_(e) are independently hydrogen, alkyl, or together with thecarbon atom to which they are attached may form a 1,1-cycloalkyl group;provided that when X is straight chain alkylene and Q is oxygen, then Zrepresents a heterocyclyl including at least two heteroatoms; or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein R' and R" are H.
 3. A compound according to claim 2, wherein Xis a lower alkylene which can be branched and substituted by at leastone CH₃, CH₃ CH₂, Cl, F, CF₃ or CH₃ O.
 4. A compound according to claim2, wherein Z is ##STR46##
 5. A compound of the formula ##STR47##wherein: K is CH;Q is CH₂ or O; T is ##STR48## or R₃ O--CH₂ ; X is astraight or branched chain alkylene, cycloalkylene or cycloalkenylenegroup; Y is NR₄, O or S;a=0 or 1; Z is a substituted or unsubstitutedthiazolyl group or a substituted or unsubstituted benzothiazolyl group;R₁, R₂, R₃, and R₄ are independently H, alkyl, aryl or heterocyclyl; andR' and R" are independently hydrogen, alkyl, aralkyl, carbamoyl,alkylcarbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl,aralkoxycarbonyl, aryloxycarbonyl, or R' and R" together may form##STR49## where R_(c) is hydrogen or alkyl, ##STR50## where R_(d) andR^(e) are independently hydrogen, alkyl, or together with the carbonatom to which they are attached may form a 1,1-cycloalkyl group; or apharmaceutically acceptable salt thereof.
 6. A compound as claimed inclaim 4, wherein X represents the alkylene moiety CR₉ H--CH₂, wherein R₉hydrogen, lower alkyl, halo, halo lower alkyl or lower alkoxy.
 7. Acompound as claimed in claim 6, wherein the alkylene carbon to which R₉is bonded is a chiral center.
 8. A compound according to claim 7,wherein R₉ is methyl or ethyl.
 9. A compound according to claim 7,wherein said chiral center is substantially exclusively R.
 10. Acompound according to claim 1 wherein: K is CH; Q is CH₂ ; and T is R₁R₂ N--C═O.
 11. A compound according to claim 2 which is[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(5-chloro-2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,[1S-[1α,2β,3β,4α]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,[1S-1α,2β,3β,4α]]-4-[7-[[2-(2-thienyl)-1-isopropylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,[1S-[1α,2β,3β,4α(S*)]]-4-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(2-thienyl)-1-methylethyl]amino]-3H-imidazo[4,5b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,or[1S-[1α,2β,3β,4α]]-4-[7-[[2-(5-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-carboxamide,or a pharmaceutically acceptable salt thereof.
 12. A composition fortreating a cardiovascular disease marked by hypertension of myocardialischemia, said composition comprising an antihypertensive effectiveamount, or an anti-ischemic effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier thereof.
 13. A methodfor treating a patient suffering from hypertension, comprisingadministering to said patient an effective blood pressure loweringamount of a compound according to claim
 1. 14. A method for treating apatient suffering from myocardial ischemia, comprising administering tosaid patient an effective antiischemic amount of a compound according toclaim
 1. 15. A compound according to claim 11 which is[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,or a pharmaceutically acceptable salt thereof.
 16. A compositionaccording to claim 12 comprising[1S[1α,2β,3β,4α(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,or a pharmaceutically acceptable salt thereof.
 17. A method according toclaim 13, wherein the compound administered is[1S-[1α,2β,3β,4'(S*)]]-4-[7-[[2-(3chloro-2-thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,or a pharmaceutically acceptable salt thereof.
 18. A method according toclaim 14, wherein the compound administered is[1S-[1α,2β,3β,4α(S*)]]-4-[7-[[2-(3-chloro-2-thienyl-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide,or a pharmaceutically acceptable salt thereof.